The present disclosure is broadly concerned with drug delivery systems. More particularly, it is concerned with drug carrying nanocomposite particles including magnetic nanoparticles and a biocompatible polymer that is biodegradable.
Conventional chemotherapies for cancers and inflammatory diseases act systemically, causing severe side effects throughout a patient's body. The cytotoxic effects are diffuse, and extend to healthy cells as well as malignant or inflamed cells. These chemotherapies also lack the ability to boost uptake of their therapeutic agents into the affected tissues, where it can be most effective. Known chemotherapies are also unable to provide slow-release delivery of pharmaceutical agents to targeted sites such as tumors and areas of inflammation.
Primary bone cancers, including osteosarcoma, chondrosarcoma, and Ewing's sarcoma, are highly malignant tumors derived from osteogenic cells or chondrocytes. Osteosarcoma is one of the most common primary malignant tumors seen in orthopedic surgery, with high mobility in young adults and adolescents. Despite intensive treatment, including adjuvant chemotherapy to localize the tumor before surgery and prevent recurrence and metastasis after surgery, wide excision of tumors, and amputation of diseased limbs, approximately half of the patients die within five years. Other cancers, such as breast, skin, liver, lung, prostate, throat and kidney, could also benefit from close targeting of chemotherapy. Recent studies have suggested that the efficiency of chemotherapy in treatment not only depends on the anti-cancer drug itself but that it is also critically associated with the drug delivery and distribution, local site concentration, and duration of effective dose. However, maintenance of effective concentrations of chemotherapy agents at a local tumor site without broadly killing remote normal cells remains an unsolved task.
Certain inflammatory diseases, such as rheumatoid arthritis (RA), experience limited treatment success with conventional chemotherapy, even when it is employed in combination with surgery and implants. RA is a chronic autoimmune disease that affects about 1% of the world population, including 1.3 million Americans. In any age group, women are affected three times more often than men. Although there are many available courses of treatment for managing the symptoms, and patients can go into remission between flares, no cure is currently available. The disease is characterized by inflammation of the lining, or synovium. After the appearance of the disease, erosive joint destruction usually starts within 1-2 years and continues. RA usually leads to long-term joint damage, resulting in chronic pain, loss of function and mobility, and disability. Although RA is most commonly known to affect joints, it is a systemic disease that can also affect organs and tissues and results in early mortality. Current therapies for RA include a range of pharmaceutical agents. Failure to respond adequately to medications and other possible treatments frequently requires surgery to correct severely affected joints. Despite intensive treatment with such drugs, most RA patients suffer for extended periods of time and experience substantial loss of function and mobility. Recent studies have suggested that the efficiency of RA drugs in treatment is critically associated with the drug delivery and distribution, local site concentration, and effective duration, none of which are effectively addressed with conventional RA chemotherapy.
Nanomaterials exhibit many novel physical properties such as optical, electronic, magnetic and structural properties, which are not found in bulk materials. These properties could enable nanomaterials to be used for detection of desired cells by covalently linked peptides, proteins, nucleic acids, and small-molecule ligands. Various attempts have been made to develop nanoparticles for use in targeted drug delivery systems. Detection is a crucial step in developing such systems since it is necessary to verify concentration of the nanoparticles at the selected location. Detection of nanoparticles used in drug delivery is problematic, however, because of the extremely small particle size. Biodegradable nanoparticles are especially difficult to detect, because of the inherent property of degradation. Once the nanoparticles are degraded, there is no residual “footprint” that can be detected, aside from the presumptive results of the drug release.
Superparamagnetic iron oxide nanoparticles have been used as contrast agents in cancer detection and have been widely studied for use in drug delivery. Metal and semiconductor nanoparticles have been used for molecular profiling studies and multiplexed biological assays. Quantum Dots (QD) have been used extensively in fluorescent probes for in vivo biomolecular and cellular imaging. However, difficulties have been reported in detecting the QD probes in living animals and QD have been reported to be toxic if allowed to aggregate on the cell surface. Attempts have been made to use amphiphilic triblock copolymer to prevent aggregation and degradation of QD within the in vivo environment. There have also been recent attempts to develop targeted therapeutic systems using external forces, including magnetic fields, ultrasound, electric fields, temperature, light, and mechanical forces to concentrate drugs in a target location. Magnetically targeted oral drug delivery of polymeric microparticles infused with magnetic nanocrystals has been shown to increase the efficiency of protein drugs used to increase bioavailability of insulin. Some problems or difficulties encountered when using currently available magnetic drug delivery systems is that the systems require amounts of magnetic material that may cause inflammation, cytotoxicity or other harm to the tissues. Such magnetic systems may also be subject to inefficiency in migration.
Albumin, the major plasma protein in human blood, plays a key role in the transport of nutrients and metabolites as well as maintenance of the colloidal osmotic pressure of blood. Previous investigations have shown that tumors and some inflammatory disorders metabolize substantial amounts of albumin. In particular, tumors and RA are known to metabolize albumin for a source of nitrogen and energy. Other studies have shown that tumor-bearing animals accumulate albumin in tumors because of their altered physiology and metabolism, including fluid phase endocytosis. Tests of the distribution of albumin in arthritis mice by injection of fluorescence-labeled human serum albumin have revealed increased labeled-albumin concentration in arthritic digits in comparison with digits without arthritis. In a scintigraphic image of the entire mouse, there was a higher concentration of labeled albumin in the kidneys and paws. Inclusion of albumin in nanocomposite materials as a targeted drug delivery system may increase the concentration of the therapeutic agent directly in the affected tissue. However, in order to develop such a system, it will be necessary to overcome the problem of organ concentration so that albumin is able to pass through organs such as kidneys and liver without absorption.
What is needed is a targeted drug delivery system and/or composition for cancers and inflammatory diseases that can deliver effective quantities of pharmaceutical agents to closely targeted sites and release them in a controlled manner over an extended period of time. What is also needed is a system or composition comprising a polymer, preferably a biodegradable polymer, a biological targeting composition, a magnetic nanoparticle, and a drug. What is further needed is such a system or composition involving a biodegradable polymer, a biological targeting component, a magnetic nanoparticle, and a cancer drug for the treatment of cancers with aggressive tumors such as bone cancer. What is still further needed is such a system or composition involving a biodegradable polymer, a biological targeting component, a magnetic nanoparticle and an RA drug for the treatment of inflammation in RA. What is also needed is an anti-cancer or RA drug-carrying magnetic nanocomposite that will migrate to a local tumor site or site of inflammation by both external force such as a high magnetic field, an internal force, such as interaction of a biological targeting component with the tumor or affected tissues, or both, and subsequently release the drug in a targeted and concentrated manner. What is still further needed is a biological targeting agent that will reduce the amount of magnetic nanoparticles used during the fabrication of the composite nanoparticle thereby reducing interaction between the magnetic agent and the tumor or site of inflammation. There is also a need for a biological targeting agent that can be used in a composite nanoparticle drug delivery system to draw a drug directly into the affected tissue. What is still further needed is a highly concentrated and persistent antitumor or inflammatory agent that will slow or halt the growth of aggressive primary tumors such as osteosarcomas and prevent tumor metastasis and inflammation.